Understanding individual differences in the development of extra-pyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment.
We performed genome-wide association studies to search for genetic susceptibility to EPS. Our sample consists of 738 schizophrenia patients, genotyped for 492K SNPs. We studied three quantitative measures of antipsychotic adverse drug reactions, the Simpson-Angus scale (SAS) for parkinsonism, the Barnes akathisia rating scale, and the abnormal involuntary movement scale (AIMS) as well as a clinical diagnosis of probable tardive dyskinesia.
Two SNPs for SAS, rs17022444 and rs2126709 with p=1.2×10-10 and p=3.8×10-7, respectively, and one for AIMS, rs7669317 with p=7.7×10-8, reached genome-wide significance (q-value <0.1). Rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (q-value <0.5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1 which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia.
Although our findings require replication and validation, this study demonstrates the potential of GWAS to discover genes and pathways that mediate adverse effects of antipsychotics.